1. Field of the Invention
The present invention relates to a method for treating pain and brain perfusion abnormalities by the administration of mixed opioid agonist-antagonists.
2. Brief Description of the Background Art
Cocaine abuse has reached epidemic proportions in the general population (Kozel, N. J., et al., Science 234:970 (1986); and has also increased among heroin-dependent persons, including those in methadone maintenance treatment programs (Kosten, T. R., et al., Am. J. Drug Alcohol Abuse 12:1 (1986); Kaul, B., et al., ibid. 8:27 (1981)). The medical and neurological complications associated with cocaine and polydrug abuse are well known. Several studies in the last few years have demonstrated regional abnormalities in cerebral blood flow (rCBF) and metabolism in chronic and acute cocaine use (Holman et at., J. Nucl. Med. 33:1312-1315 (1992); Holman et al., J. Nucl. Med. 34:723-727 (1993)). For example Tc-99 mHMPAO single photon emission computed tomography (SPECT) has been used to demonstrate focal perfusion abnormalities, especially in interior brain structures, in exclusively cocaine-dependent men, and in cocaine and polydrug dependent men. It has also been reported that the abnormal brain perfusion patterns associated with polydrug and chronic cocaine users are indistinguishable from those in early-AIDS dementia complex (Holman et al., J. Nucl. Med. 33:1312-1315 (1992)).
The aforementioned alterations in regional blood flow is attributed to the vasoconstrictive activity of cocaine. Vasoconstriction has been reported in the coronary arteries in association with cocaine administration (Ascher et al., J. Cardiol. 61:939-941 (1988)) and cocaine has been reported to cause elevated blood pressure and heart rate as well as focal cerebral lesions such as intracranial or subarachnoid hemorrhage and infarction (Jacobs et al., Arch. Neurol. 44:165-168 (1987)).
Chronic cocaine use also results in generalized multifocal alternations in rCBF which occur without underlying structural damage (Volkow et al., Br. J. Psych. 152:641-648 (1988); Tumeh et al. , Radiology 176:821-824 (1990)). A study employing high-resolution imaging techniques detected multiple small and moderate perfusion defects in the cortex, with altered blood flow to the basal ganglia and a generalized reduction in cerebral uptake of radio tracers that distribute proportionately to blood flow (Donahoe et al., Psychological, Neuropsychiatric and Substance Abuse Aspects of AIDS, New York, Raven Press, p. 139-143 (1988)). Since most of the patients involved in this study had normal structural findings on CT and MRI scans, the perfusion defects could not be attributed to an underlying infarction and hemorrhage. Moreover, preliminary reports have suggested that these changes in cerebral blood flow are not responsive to short-term withdrawal of drugs and therefore may be a permanent result of cocaine abuse (Strickland et al., J. Nucl. Med. 32:1021 (1991); Volkow et al., J. Nucl. Med. 32:960 (1991)).
In another study, a substantial improvement in perfusion to cortical areas was observed in cocaine polydrug abusers, with a 45% increase in blood flow after 3-4 weeks of abstention. However, rCBF did not completely return to normal in 9 our of 10 patients tested. While buprenorphine was administered during the period of abstention, it was believed the improvement was due to the abstention, and not the buprenorphine (Holman et al., J. Nucl. Meal. 34:723-727 (1993)). These findings of normal structure and partially reversible perfusion abnormalities in cocaine polydrug users support the hypothesis that the observed cortical perfusion defects are due to vasoconstriction, a phenomenon observed in the heart and other organs of cocaine dependent patients (Ascher et al., Am. J. Cardiol. 61:931-941 (1988)).
It is also known that opioid, agonist and antagonists, have an adverse effect on cerebral blood flow and metabolism in the normal and ischemic brain. Several groups have reported that opiates, such as morphine or heroine, decrease global or regional CBF after acute administration in normal laboratory animals (Sandor et al., Life Sci. 39:1657-1665 (1986); Grandison et al. , Brain Res. 291:301-308 (1984); Hoehner et al. , Anesth. Analg. 76:266-273 (1993)). Others have reported similar decreases in cerebral metabolism in dogs (Matsumiya et al., Anesthesiology 59:179-181 (1983)) and in chronic polydrug abusing men studied with positron emission tomography (London et al., Arch. Gen. Psychi. 47:73-81 (1990)). As mentioned above, cocaine abuse among heroin-dependent subjects has increased, and the abuse of both drags in polydrug dependent patients further compromises cerebral vascular circulation.
The effect of the opioid antagonist naloxone is less clear. Some have shown that it increases rCBF in normal laboratory animal brain (Turner et al., Neurosurgery 4:276-282 (1984); Phillis et al., Neurosurgery 7:596-609 (1985)), while causing vasodilatation of pial vessels and increasing cerebral blood volume (Turner et al., Neurosurgery 15:192-197 (1984); Kobari et al., J. Cereb. Blood Flow Metab. 5:34-39 (1985)). It has also been shown in similar models, that naloxone reverses the decrease in CBF caused by morphine, and that it improves CBF in ischemic brain tissue (Hariri et at., Life Sci. 39:1657-1665 (1986); Turcani et al., Thromb. Res. 44:817-828 (1986)) and improves neurological deficit (Baskin et al., Brain Res. 290:289-296 (1984)). However, others have reported the opposite, that it causes a decrement in CBF in normal brain (Turcani et al., Thromb. Res. 44:817-828 (1986); Trusk et al., Brain Res. 406:238-245 (1987)), that it offers no clinical (Kastin et al. , Pharmacol. Biochem. Behav. 17:1083-1085 (1982)) or perfusion (Hubbard et al., J. Neurosurg. 59:237-244 (1983); Gaines et al., Neurosurgery 14:308-314 (1984)) benefit, or actually impairs CBF in ischemic brain (Levy et al., Life Sci. 31:2205-2208 (1982)) or that it dangerously increases cerebral metabolism in this injured tissue (Kobayashi et al., Neurochirurgia 35:69-73 (1992)).
Another population at risk for brain perfusion abnormalities, and which experiences a disproportionate amount of pain, is geriatric patients. Pain is common in the elderly, occurring in as many as 25-50% of community-dwelling people over age 60 (Ferrel et al., Comprehensive Therapy 17(8):53-58 (1991)). It has been shown that the age-associated morbidity of pain is two-fold greater (250/1000 vs 125/1000) in individuals over age 60 compared to individuals less than age 60 (Crook et al., Pain 18:299-314 (1984)).
Many painful diseases are, in fact, more common in elderly populations. Arthritis may effect 80% of people over age 65, and most will suffer significant pain. Cancer is also a major contributor to pain syndromes, with more than 60% of cancers occurring in the over-65 age group. Severe pain is present in one-third to one-half of patients undergoing cancer therapy and in more than two-thirds with advanced disease (Levin et al., Cancer 56:2337 (1985)). Other specific pain syndromes known to effect the geriatric population disproportionately include herpes xoster, temporal arteritis, polymyalgia rheumatica, and atherosclerotic peripheral vascular disease (Gordon, R. S., JAMA 241 (23):2119-2492 (1979)).
Epidemiological studies focusing on nursing home residents reveal that a significant proportion of the "institutionalized" elderly population also suffer from pain syndromes. In the nursing home population, pain reports range from 49%-83% with a predominance of musculoskeletal causes of pain, especially osteoarthritis. It has also been reported that 83% of selected nursing home subjects have a pain "problem" (Roy et al., Can. Fam. Phys. 32:513-516 (1986)). In another study of five nursing homes in Singapore it was reported that 39% of the residents had a prevalence of pain (Lau-Tin et al., Sing. Med. J. 29:164-167 (1988)).
A study conducted at the Geriatric Research Education and Clinical Center found that 71% of nursing home residents had a pain compliant and 33% of those patients described constant, unrelenting pain. Two-thirds of patients had intermittent pain, 50% of which occurred on a daily basis. Forty percent of subjects complained of low back pain, 38% had arthritis pain of the appendicular skeleton, 14%, pain in a previous fracture site, 11%, neuropathies, 9% had leg cramps and a variety of common pain problems. Pain appeared to directly effect more advanced activities of daily living. Patients often reported difficulty in ambulation and impaired attendance at social activities. Sleep disturbance was also commonly associated with pain among nursing home residents (Farrell et al., J. Am. Geriatr. Soci. 38(4):409-414 (1990)).
The geriatric population also suffers from cerebrovascular disease, which is the third leading cause of death after heart disease and cancer in developed countries. In adults, it is the most lethal and disabling of the neurologic diseases. It has an overall prevalence of 794 per 100,000, and 5% of the population over age 65 has at one time in their lives had a stroke. In the United States, it is estimated that more than 400,000 patients are discharged each year from hospitals after a stroke (Petersdoff, et al., eds., Harrison's Principles of Internal Medicine, 11th ed., McGraw-Hill, publisher, New York, N.Y., p. 1930 (1987)).
Cerebrovascular insufficiency implicates one or more of the blood vessels of the brain in a pathologic process. The process may be intrinsic to the vessel, as it is in atherosclerosis, or the process may start at a remote site, as occurs when decreased perfusion pressure or increased blood viscosity results in inadequate blood flow through a vessel. Vascular lesions involved in cerebrovascular disease tend to be silent until critical narrowing occurs, which can result in occlusive cerebral disease and ischemia.